Islet transplantation for type 1 diabetes (T1D) is experiencing increasing clinical success, but its applicability is currently limited by the need for chronic immunosuppression the amount of islets needed per recipient and the transplantation site. Encapsulation may allow addressing many shortcomings but so far traditional 1000 m diameter capsules have not been shown effective. Most likely, this is because large capsules limit nutrient transport leading to loss of functionality and, ultimately, death of the islet graft. Recently, we developed an encapsulation technology that allows `wrapping' single islets with a thin (up to 10 m) layer of biomaterial, generating capsules that `conform' to the islet size and shape. By reducing the diffusion distance 10-fold, conformal coating (CC) increases nutrient transport to the encapsulated islets. By reducing the graft volume from ~500 mL to ~3 mL, CC also allows transplantation in vascularized sites - not limited to the intraperitoneal cavity - further maximizing nutrient transport. Our computational models predict that, contrary to traditional microcapsules, CC grafts at vascularized sites prevent central necrosis due to hypoxia, and allow physiological glucose-stimulated insulin release. In mice, we showed prompt T1D reversal and long-term euglycemia after transplantation of fully MHC-mismatched CC grafts without immunosuppression. Accordingly, we hypothesize that our unique CC technology can allow long-term function of islet transplantation in preclinical models of T1D without the need for immunosuppression. Further, we hypothesize that by minimizing capsule thickness and increasing nutrient transport yet protecting the graft, we can minimize the dose of islets required to reverse T1D. In Aim 1, we will complete the preclinical evaluation of the basic CC platform and determine the mechanisms associated with graft success. We will establish the efficacy of CC capsules in maintaining long- term function without immunosuppression in allo and auto-immune settings (Aim 1.1). We will also establish the efficacy of CC encapsulation of human islets in preclinical models (Aim 1.2). In parallel, in Aim 2, we will enhance the translational potential of the CC platform by engineering features that minimize the dose of CC islets required for T1D reversal. We will achieve the ideal balance between nutrient transport and immunoisolation by minimizing CC thickness and incorporating nanocarriers of immunomodulatory molecules (Aim 2.1). We will also increase CC graft revascularization to improve inbound and outbound transport by using clinically translatable pro-angiogenic scaffolds (Aim 2.2). Finally, we will increase oxygen diffusivity in CC to enhance islet function by incorporating oxygen nanocarriers. This necessary preclinical work will position the CC technology for translation and application in future nonhuman primate and clinical trials. If successful, this technology can significantly impact the field by promoting graft survival, the success rate of islet transplantation yet reducing the need for islets and immunosuppression.